1. Field of the Invention
This invention relates to compositions and formulations of oligonucleotides and surfactants, which are highly effective for the prevention and treatment of diseases and conditions associated with difficult breathing, bronchoconstriction, impeded airways, allergy(ies) and inflammation of the lungs.
2. Description of the Background
Adenosine A1-mediated diseases and conditions, such as asthma and Acute Respiratory Distress Syndrome (ARDS), among others, are common diseases in industrialized countries, and in the United States alone account for extremely high health care costs. These diseases or conditions have recently been increasing for an alarming rate, both in terms of prevalence and mortality. Occupational asthma is predicted to be the preeminent occupational lung disease in the next decade. In many of these, the underlying causes remain poorly understood.
Adenosine, a natural nucleoside, may constitute an important natural mediator of bronchial asthma and ARDS. The potential role of adenosine in these diseases or conditions is supported by experimental findings that, for example and in contrast to normal individuals, asthmatics respond to aerosolized adenosine with marked bronchoconstriction. Similarly, asthmatic rabbits produced using the dust mite allergic rabbit model of human asthma also were shown to respond to aerosolized adenosine with marked bronchoconstriction, while non-asthmatic rabbits showed no response. Recent work using this model system has suggested that adenosine-mediated bronchoconstriction in asthma is mediated through the stimulation of the adenosine A1 receptor. Other experimental data suggest the possibility that adenosine receptors may also be involved in allergic and inflammatory responses.
Adenosine receptor antagonists, such as theophylline, are known to counter adenosine-mediated bronchoconstriction in asthmatic rabbits. Pre-treatment with another adenosine A1-specific receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX), also inhibited adenosine-mediated bronchoconstriction and bronchial hyper-responsiveness in an allergic rabbit model. The therapeutic potential, however, of currently available adenosine A1 receptor-specific antagonists is drastically limited by their toxicity. Theophylline, for example, although widely used in the treatment of asthma, may result in frequent and significant toxicity because of its narrow therapeutic dose range.
The availability of a novel strategy to prevent and/or counter adenosine receptor-associated effects of disorders and conditions associated with symptoms such as pulmonary bronchoconstriction, impeded respiration. Inflammation and allergy(ies), among others, of great practical importance. Such technology is clearly applicable to the treatment of ailments including Acute Respiratory Disorder Syndrome (ARDS), asthma, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), and cancers such as leukemias, lymphomas, carcinomas, and the like, including colon cancer, breast cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastases, etc., as well as all types of cancers which may metastasize or have metastasized to the lung(s), including breast and prostate cancer would clearly find an immediate therapeutic application. Similarly, a composition and method which are suitable for administration before, during and after other treatments, included radiation, chemotherapy, antibody therapy, phototherapy an cancer, and other types of surgery, and that may be effectively administered preventatively, prophylactically or therapeutically, and in conjunction with other therapies, or by itself for conditions without known therapies or as a substitute for therapies that have significant negative side effects is also of immediate clinical application.
The present invention relates to a pharmaceutical composition effective to alleviate bronchoconstriction, allergy and/or inflammation, comprising a surfactant, and an anti-adenosine A1, A2b or A3 receptor or anti-adenosine A2a receptor oligonucleotide exhibiting at least some adenosine A1, A2b or A3 receptor inhibitory activity, analogues thereof which bind to thymidine but evidence either reduced adenosine content or reduced adenosine receptor activating activity, combinations thereof, physiologically acceptable salts thereof or mixtures thereof. The composition of this invention may be formulated for administration by various different routes, such as topical and systemic, e.g. oral, parenteral, inhalable, and the like, and are generally administered in amounts which prevent or reduce adenosine receptor associated side effects such as bronchoconstriction, allergy(ies), inflammation and airway obstruction, among others. The present compositions and formulations, thus, are suitable for the prevention and alleviation of adenosine receptor associated bronchoconstriction, allergy and/or inflammation and, therefore, in the treatment of Acute Respiratory Disorder Syndrome (ARDS), asthma, side effects associated with adenosine administration in SupraVentricular Tachycardia (SVT) and in stress tests to hyper-sensitized individuals, ischemia, renal damage or failure induced by certain drugs, respiratory distress syndrome, pain, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, chronic obstructive pulmonary disease (COPD), cancers such as leukemias, lymphomas, carcinmos, and the like, including colon cancer, breast cancer, lung cancer, pancreatic cancer, hepatocellular carcinoma, kidney cancer, melanoma, hepatic metastases, etc., as well as all types of cancers which may metastasize or have metastasized to the lung(s), including breast and prostate cancer, among others. The present technology is also applicable in conjunction with other procedures and/other therapies, including other therapeutic agents such as antibody therapy and chemotherapy, among others, radiation, phototherapy, and cancer and other types of surgery, and is effectively administered preventatively, prophylactically or therapeutically.